Phase I trial evaluating the antiviral agent Cidofovir in combination with chemoradiation in cervical cancer patients

// Eric Deutsch 1, 2, 3, 4 , Christine Haie-Meder 1 , Mohamed Amine Bayar 5 , Michele Mondini 4 , Melanie Laporte 6 , Renaud Mazeron 1 , Julien Adam 6 , Andrea Varga 2 , Gilles Vassal 7 , Nicolas Magne 8 , Cyrus Chargari 1, 4 , Emilie Lanoy 5, 9 , Patricia Pautier 2 , Antonin Levy 1, 2, 4 , Jean-Charles Soria 2, 3 1 Department of Radiation Oncology, Gustave Roussy Cancer Campus, Paris-Sud University, Villejuif, France 2 Drug Development Department (DITEP), Gustave Roussy Cancer Campus, Paris-Sud University, Villejuif, France 3 Paris-Sud University, Kremlin-Bicetre Medical University, DHU TORINO, SIRIC SOCRATES, LABEX LERMIT, Le Kremlin-Bicetre, France 4 INSERM U1030 Molecular Radiotherapy, Gustave Roussy Cancer Campus, Villejuif, France 5 Biostatistics and Epidemiology Unit, Gustave Roussy Cancer Campus, Villejuif, France 6 Department of Medical Biology and Pathology, Translational Research Laboratory and Biobank (UMS3655 CNRS/US23 INSERM), INSERM Unit U981, Villejuif, France 7 Department of Clinical Research, Gustave Roussy Cancer Campus, Paris-Sud University, Villejuif, France 8 Department of Radiation Oncology, Institut de Cancerologie de la Loire-Lucien Neuwirth, Saint-Priest en Jarez, France 9 Inserm U1018 Centre for Research in Epidemiology and Population Health, Paris-Sud University, Villejuif, France Correspondence to: Eric Deutsch, email: Eric.DEUTSCH@gustaveroussy.fr Keywords: phase I, HPV, Cidofovir, radiotherapy, cervix cancer Received: October 12, 2015     Accepted: March 06, 2016     Published: March 21, 2016 ABSTRACT Purpose: This phase I trial aimed to assess the safety and determine the recommended Phase II dose (RP2D) of Cidofovir combined with chemoradiotherapy in patients with stage IB2-IVA cervical cancer. Experimental design: Incremental doses (1, 2.5, 5 and 6.5 mg/kg) of IV Cidofovir were administered weekly for two weeks, and then every 2 weeks from the start of chemoradiotherapy to the initiation of utero-vaginal brachytherapy. Biological expression of HPV was analyzed during treatment and tumor response was assessed according to RECIST v1.0 criteria. Results: A total of 15 patients were treated with Cidofovir. Dose-limiting toxicities occurred in 2/6 patients at the 6.5 mg/kg dose level (G3 proteinuria, and G3 acute pyelonephritis with G3 febrile neutropenia). No toxicity occurred at the 5 mg/kg dose level, but only 3 patients received this dose due to trial interruption because of low accrual. The most frequent G3-4 adverse effects observed during the trial were: abdominal pain (n=3), infection (n=2), leuckoneutropenia (n=2), and others (n=6). No toxic death or major renal side effect occurred. The best response was that 8/9 evaluable patients achieved a complete response (89%). In the intention to treat population, the 2-year overall and progression-free survival rates were 93% and 76%, respectively. Biological monitoring of HPV-related markers (decreased p16 expression, and increased p53 and pRb levels) was possible on sequential tumor biopsy samples. The genomic alterations identified were PIK3CA (n=5; one also had a KRAS mutation), and HRAS (n=1) mutations. Conclusion: Cidofovir at a dose of 5mg/kg combined with chemoradiotherapy appeared tolerable and yielded tumor regressions. Due to early trial interruption, the RP2D was not confirmed.